Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin.
- 作者列表："Herum KM","Romaine A","Wang A","Melleby AO","Strand ME","Pacheco J","Braathen B","Dunér P","Tønnessen T","Lunde IG","Sjaastad I","Brakebusch C","McCulloch AD","Gomez MF","Carlson CR","Christensen G
:Background Pressure overload of the heart occurs in patients with hypertension or valvular stenosis and induces cardiac fibrosis because of excessive production of extracellular matrix by activated cardiac fibroblasts. This initially provides essential mechanical support to the heart, but eventually compromises function. Osteopontin is associated with fibrosis; however, the underlying signaling mechanisms are not well understood. Herein, we examine the effect of thrombin-cleaved osteopontin on fibrosis in the heart and explore the role of syndecan-4 in regulating cleavage of osteopontin. Methods and Results Osteopontin was upregulated and cleaved by thrombin in the pressure-overloaded heart of mice subjected to aortic banding. Cleaved osteopontin was higher in plasma from patients with aortic stenosis receiving crystalloid compared with blood cardioplegia, likely because of less heparin-induced inhibition of thrombin. Cleaved osteopontin and the specific osteopontin peptide sequence RGDSLAYGLR that is exposed after thrombin cleavage both induced collagen production in cardiac fibroblasts. Like osteopontin, the heparan sulfate proteoglycan syndecan-4 was upregulated after aortic banding. Consistent with a heparan sulfate binding domain in the osteopontin cleavage site, syndecan-4 was found to bind to osteopontin in left ventricles and cardiac fibroblasts and protected osteopontin from cleavage by thrombin. Shedding of the extracellular part of syndecan-4 was more prominent at later remodeling phases, at which time levels of cleaved osteopontin were increased. Conclusions Thrombin-cleaved osteopontin induces collagen production by cardiac fibroblasts. Syndecan-4 protects osteopontin from cleavage by thrombin, but this protection is lost when syndecan-4 is shed in later phases of remodeling, contributing to progression of cardiac fibrosis.
: 背景心脏压力超负荷发生在高血压或瓣膜狭窄患者中，由于活化的心脏成纤维细胞过度产生细胞外基质而诱导心脏纤维化。这最初为心脏提供了必要的机械支持，但最终会损害功能。骨桥蛋白与纤维化相关; 然而，潜在的信号机制还不是很清楚。在此，我们研究了凝血酶切割的骨桥蛋白对心脏纤维化的影响，并探讨了 syndecan-4 在调节骨桥蛋白切割中的作用。方法和结果在主动脉缩窄小鼠压力超负荷心脏中，骨桥蛋白被凝血酶上调和切割。与血液心脏停搏液相比，接受晶体液的主动脉瓣狭窄患者血浆中裂解的骨桥蛋白较高，可能是因为肝素诱导的凝血酶抑制较少。裂解的骨桥蛋白和凝血酶裂解后暴露的特异性骨桥蛋白肽序列 RGDSLAYGLR 均诱导心脏成纤维细胞产生胶原。与骨桥蛋白一样，主动脉缩窄后硫酸乙酰肝素蛋白多糖 syndecan-4 上调。与骨桥蛋白裂解位点的硫酸乙酰肝素结合域一致，发现 syndecan-4 与左心室和心脏成纤维细胞中的骨桥蛋白结合，并保护骨桥蛋白免受凝血酶的裂解。Syndecan-4 细胞外部分的脱落在后期重塑阶段更为突出，此时分裂的骨桥蛋白水平增加。结论凝血酶切割的骨桥蛋白可诱导心脏成纤维细胞产生胶原。Syndecan-4 可保护骨桥蛋白免受凝血酶的裂解，但在重塑的后期，当 syndecan-4 脱落时，这种保护作用就会丧失，有助于心脏纤维化的进展。
METHODS:BACKGROUND:Hypertensive disorders of pregnancy (HDP) increase cardiovascular disease (CVD) risk. Pregnancy morbidities, including preeclampsia, and CVD are common in systemic lupus erythematosus (SLE). Possible connections are important to explore. In a population-based cohort, we investigated whether HDP is associated with a higher risk of cardiovascular outcomes separately in SLE and non-SLE to examine the role of SLE. METHODS:We identified first singleton births in the Medical Birth Register (1987-2012) among mothers with SLE and a large general population comparison group. Discharge diagnoses for HDP, cardiovascular outcomes, and hypertension in the Patient Register were identified using ICD codes. We estimated adjusted hazard ratios and 95% confidence intervals (HR, 95% CI) of the association between HDP and outcomes, in separate models in women with and without SLE. We then evaluated additive and multiplicative effect modification using relative excess risk due to interaction and Cox models jointly accounting for SLE and HDP, respectively. Mediation analysis estimated the proportion of the association between SLE and outcome explained by HDP. RESULTS:HDP were more common in SLE pregnancies (20% vs 7%). In SLE, HDP were associated with a two-fold higher rate of cardiovascular outcomes and three-fold higher rate of incident hypertension. HDP mediated 20% of the latter association. In women without SLE, HDP was associated with higher hypertension incidence later in life. CONCLUSION:In women with and without SLE, HDP were associated with a three-fold higher rate of hypertension. In SLE, women with HDP developed cardiovascular outcomes twice as often as women without HDP.
METHODS:BACKGROUND:'Neuronal precursor cell expressed developmentally down-regulated 4-like' (NEDD4L) is considered a candidate gene for hypertension-both functionally and genetically-through the regulation of the ubiquitination of the epithelial sodium channel (ENaC). This study explores the relationship between genetic variation in NEDD4L and hypertension with chronic kidney disease (CKD) in the southeastern Han Chinese population. METHODS:We recruited 623 CKD patients and measured ambulatory blood pressure monitoring (ABPM), and the rs4149601 and rs2288774 polymorphisms in NEDD4L were genotyped using qPCR. RESULTS:For rs4149601, significant differences in genotype frequencies in an additive model (GG vs GA vs AA) were observed between normotensive patients and hypertensive patients when hypertension was classified into ambulatory hypertension, clinical hypertension and ambulatory systolic hypertension (P = 0.038, 0.005 and 0.006, respectively). In a recessive model (GG+GA vs AA), the frequency of the AA genotype of rs4149601 in the hypertension groups were all higher than that in the normotensive groups. The genotype distribution of rs2288774 did not differ significantly between the normotensive and hypertensive patients. In both the full cohort and the propensity score matching (PSM) cohort, the AA genotype of rs4149601 (compared to the GG+GA genotype group) was independently correlated with ambulatory hypertension, clinical hypertension and ambulatory systolic hypertension by multivariate logistic regression analysis. CONCLUSIONS:The present study indicates that the AA genotype of rs4149601 associates with hypertension in CKD. Consequently, the rs4149601 A allele might be a risk factor for hypertension with CKD.
METHODS:BACKGROUND:The burden of hypertension in many low-and middle-income countries is alarming and requires effective evidence-based preventative strategies that is carefully appraised and accepted by key stakeholders to ensure successful implementation and sustainability. We assessed nurses' perceptions of a recently completed Task Shifting Strategy for Hypertension control (TASSH) trial in Ghana, and facilitators and challenges to TASSH implementation. METHODS:Focus group sessions and in-depth interviews were conducted with 27 community health nurses from participating health centers and district hospitals involved in the TASSH trial implemented in the Ashanti Region, Ghana, West Africa from 2012 to 2017. TASSH evaluated the comparative effectiveness of the WHO-PEN program versus provision of health insurance for blood pressure reduction in hypertensive adults. Qualitative data were analyzed using open and axial coding techniques with emerging themes mapped onto the Consolidated Framework for Implementation Research (CFIR). RESULTS:Three themes emerged following deductive analysis using CFIR, including: (1) Patient health goal setting- relative priority and positive feedback from nurses, which motivated patients to make healthy behavior changes as a result of their health being a priority; (2) Leadership engagement (i.e., medical directors) which influenced the extent to which nurses were able to successfully implement TASSH in their various facilities, with most directors being very supportive; and (3) Availability of resources making it possible to implement the TASSH protocol, with limited space and personnel time to carry out TASSH duties, limited blood pressure (BP) monitoring equipment, and transportation, listed as barriers to effective implementation. CONCLUSION:Assessing stakeholders' perception of the TASSH implementation process guided by CFIR is crucial as it provides a platform for the nurses to thoroughly evaluate the task shifting program, while considering the local context in which the program is implemented. The feedback from the nurses informed barriers and facilitators to implementation of TASSH within the current healthcare system, and suggested system level changes needed prior to scale-up of TASSH to other regions in Ghana with potential for long-term sustainment of the task shifting intervention. TRIAL REGISTRATION:Trial registration for parent TASSH study: NCT01802372. Registered February 27, 2013.